The broad, long term objectives of the proposed studies are to determine the fundamental mechanisms by which cocaine leads to adverse and potentially fatal cardiac effects. The adverse cardiac effects of interest are cocaine-induced arrhythmias and sudden death. It has become increasingly clear over the past decade that cocaine use can lead to myocardial infarction and sudden death in normal hearts as well as those with coronary artery disease. Although cardiovascular effects of cocaine have been studied, an integrated approach to the problem of cocaine- induced arrhythmias and sudden death has not been undertaken. The overall aim of this study is to determine the basic in vivo mechanisms by which cocaine leads to cardiac arrhythmias and/or sudden death. The experimental paradigm in which the mechanism of cocaine-induced adverse cardiac effects will be studied is the conscious canine model of sudden cardiac death. This paradigm is well established in our laboratory. We hypothesize that in conscious dogs cocaine increases cardiac work and myocardial oxygen demand through positive inotropic and chronotropic effects. Additionally, cocaine reduces myocardial blood flow by increasing vascular tone, and alters cardiac electrophysiologic stability. In the setting of a previous myocardial infarction, cocaine-induced changes in hemodynamic and electrophysiologic parameters predispose the heart to ventricular arrhythmias. We will determine the proarrhythmic and profibrillatory mechanisms of cocaine in surgically instrumented conscious canine preparations that are at a low or high risk of developing ventricular fibrillation. We aim to determine the effect of cocaine on the susceptibility of the heart to programmed electrical stimulation-induced ventricular arrhythmias. Hemodynamic effects of cocaine will be studied systemically and at the level of the coronary circulation. Electrophysiologic effects of cocaine will be studied using Lead II, ventricular excitability and refractory period determinations, and local electrical activity in distinct (infarcted and non-infarcted) regions of the heart. Regional myocardial function will be studied by monitoring regional wall thickness using piezoelectric crystals implanted in the ventricular myocardium. Electrophysiologic, hemodynamic and functional parameters will be recorded continuously using a microcomputer/Grass Polygraph interface. To further characterize adverse effects of cocaine the ex vivo platelet aggregatory response to known platelet agonists will be assessed. To determine the acute effects of cocaine upon myocardial ultrastructural integrity plasma creatine kinase concentrations will be determined. It is anticipated that the study will characterize the arrhythmogenic potential of cocaine and determine the underlying in vivo mechanisms for these effects.